Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161)
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.14C>T (p.Pro5Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(16)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.14C>T (p.Pro5Leu)
Variation ID: 35824 Accession: VCV000035824.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117480108 (GRCh38) [ NCBI UCSC ] 7: 117120162 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Oct 20, 2024 Jun 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.14C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Pro5Leu missense NC_000007.14:g.117480108C>T NC_000007.13:g.117120162C>T NG_016465.4:g.19325C>T NG_056120.2:g.4138C>T LRG_663:g.19325C>T LRG_663t1:c.14C>T LRG_663p1:p.Pro5Leu - Protein change
- P5L
- Other names
- -
- Canonical SPDI
- NC_000007.14:117480107:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CFTR | - | - |
GRCh38 GRCh37 |
3835 | 5214 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jun 17, 2024 | RCV000029477.32 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 26, 2024 | RCV000727666.29 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004225.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 27, 2024 | RCV003473126.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 4, 2020 | RCV002284179.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Apr 3, 2024 | RCV004734531.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Nov 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854974.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163101.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002757301.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In … (more)
Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161) (less)
|
|
|
Likely pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809413.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Likely pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213361.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
likely pathogenic
(Jun 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469497.2
First in ClinVar: Jan 26, 2021 Last updated: Sep 29, 2024 |
Comment:
The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals … (more)
The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 25658530 (2015), 25754095 (2015), 21983161 (2012), 19724303 (2010), 17331079 (2007), 17137500 (2006), 9439669 (1997)), atypical/mild CF symptoms (PMIDs: 31328366 (2019), 21983161 (2012), 19318035 (2009), 17594397 (2007)), and CFTR-related disorders (PMIDs: 34996830 (2022), 33374015 (2020), 27264265 (2016), 21520337 (2011), 15758663 (2005), 11938439 (2002)). Functional studies indicate this variant has deleterious effects on CFTR protein expression and ion channel activity (PMIDs: 29805046 (2018), 18306312 (2008), 17235394 (2007)). The frequency of this variant in the general population, 0.000054 (7/128930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821843.14
First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024 |
Comment:
CFTR: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001821978.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Aug 04, 2020)
|
criteria provided, single submitter
Method: curation
|
cystic fibrosis
CFTR-related disorders
Affected status: yes
Allele origin:
germline
|
CFTR-France
Accession: SCV001169588.2
First in ClinVar: Mar 16, 2020 Last updated: Sep 24, 2022 |
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
|
|
|
Likely pathogenic
(Mar 13, 2014)
|
criteria provided, single submitter
Method: literature only
|
Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220159.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Mendelics
Accession: SCV000886149.4
First in ClinVar: May 26, 2018 Last updated: Apr 01, 2023 |
|
|
|
Pathogenic
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000074336.8
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). This variant is present in population databases (rs193922501, gnomAD 0.006%). This missense change has been observed in individuals with bronchiectasis, chronic pancreatitis, cystic fibrosis, and/or other CFTR-related disorders (PMID: 18306312, 19724303, 21520337, 21983161, 25910067). ClinVar contains an entry for this variant (Variation ID: 35824). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CFTR function (PMID: 17235394, 18306312, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562363.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a … (more)
The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74. (less)
|
|
|
Likely pathogenic
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001172271.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide … (more)
The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple individuals carrying a second CFTR alteration (six with p.F508del, two with p.W1282*, and one with p.R347P) with varying disease severity. The majority of individuals had pancreatic sufficiency, mild or no respiratory symptoms, normal lung function, and elevated sweat chloride levels (Spicuzza L et al. J. Cyst. Fibros., 2012 Jan;11:30-3; Sofia VM et al. Mol. Med., 2018 07;24:38). This variant has also been identified in multiple newborns with abnormal newborn screening results (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46; Paracchini V et al. JIMD Rep, 2012 Nov;4:17-23), as well as in an individual with idiopathic chronic pancreatitis (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In two functional studies, this variant demonstrated a reduced level of WT-CFTR protein function; in addition, the protein was predominantly localized intracellularly and demonstrated abnormal channel gating activity (Gené GG et al. Hum. Mutat., 2008 May;29:738-49; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). The p.P5L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 22, 2018). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Pathogenic
(Jun 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052127.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2024 |
Comment:
Variant summary: CFTR c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CFTR c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes. c.14C>T has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, ICP, and CF (e.g. Chirico_2014, Narzi_2007, Sanz_2010, Schneider_2007, Spicuzza_2011). Multiple authors have indicated that the variant could cause a mild form of CF. These data indicate that the variant is very likely to be associated with disease. Co-occurrence with a pathogenic variant, CFTR 5T_TG11, has been reported (Narzi_2007). At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-30% of normal activity (Thelin_2007, Gene_2008, Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9439669, 19897426, 15758663, 18306312, 17594398, 20351098, 19724303, 17594397, 20351101, 17235394, 21983161, 19318035, 11938439, 25735457, 27264265, 25658530, 28736296, 29805046, 33374015). ClinVar contains an entry for this variant (Variation ID: 35824). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Apr 03, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005362178.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The CFTR c.14C>T variant is predicted to result in the amino acid substitution p.Pro5Leu. This variant has been reported in the compound heterozygous state in … (more)
The CFTR c.14C>T variant is predicted to result in the amino acid substitution p.Pro5Leu. This variant has been reported in the compound heterozygous state in individuals with cystic fibrosis or chronic pancreatitis, typically with mild features and a second pathogenic variant that has been associated with severe forms of cystic fibrosis such as p.Phe508del (Gené et al. 2008. PubMed ID: 18306312; Thelin et al. 2007. PubMed ID: 17235394; Spicuzza et al. 2012. PubMed ID: 21983161; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies indicate this variant results in impaired CFTR function, presumably through a loss of glycosylation leading to intracellular retention of the receptor (Gené et al. 2008. PubMed ID: 18306312). However, to our knowledge there are no reports of individuals with classic cystic fibrosis who are homozygous for this variant. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Comment:
Comment:
The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 25658530 (2015), 25754095 (2015), 21983161 (2012), 19724303 (2010), 17331079 (2007), 17137500 (2006), 9439669 (1997)), atypical/mild CF symptoms (PMIDs: 31328366 (2019), 21983161 (2012), 19318035 (2009), 17594397 (2007)), and CFTR-related disorders (PMIDs: 34996830 (2022), 33374015 (2020), 27264265 (2016), 21520337 (2011), 15758663 (2005), 11938439 (2002)). Functional studies indicate this variant has deleterious effects on CFTR protein expression and ion channel activity (PMIDs: 29805046 (2018), 18306312 (2008), 17235394 (2007)). The frequency of this variant in the general population, 0.000054 (7/128930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Comment:
CFTR: PM3:Very Strong, PM2, PS3:Supporting
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). This variant is present in population databases (rs193922501, gnomAD 0.006%). This missense change has been observed in individuals with bronchiectasis, chronic pancreatitis, cystic fibrosis, and/or other CFTR-related disorders (PMID: 18306312, 19724303, 21520337, 21983161, 25910067). ClinVar contains an entry for this variant (Variation ID: 35824). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CFTR function (PMID: 17235394, 18306312, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.
Comment:
The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74.
Comment:
The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple individuals carrying a second CFTR alteration (six with p.F508del, two with p.W1282*, and one with p.R347P) with varying disease severity. The majority of individuals had pancreatic sufficiency, mild or no respiratory symptoms, normal lung function, and elevated sweat chloride levels (Spicuzza L et al. J. Cyst. Fibros., 2012 Jan;11:30-3; Sofia VM et al. Mol. Med., 2018 07;24:38). This variant has also been identified in multiple newborns with abnormal newborn screening results (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46; Paracchini V et al. JIMD Rep, 2012 Nov;4:17-23), as well as in an individual with idiopathic chronic pancreatitis (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In two functional studies, this variant demonstrated a reduced level of WT-CFTR protein function; in addition, the protein was predominantly localized intracellularly and demonstrated abnormal channel gating activity (Gené GG et al. Hum. Mutat., 2008 May;29:738-49; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). The p.P5L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 22, 2018). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Variant summary: CFTR c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes. c.14C>T has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, ICP, and CF (e.g. Chirico_2014, Narzi_2007, Sanz_2010, Schneider_2007, Spicuzza_2011). Multiple authors have indicated that the variant could cause a mild form of CF. These data indicate that the variant is very likely to be associated with disease. Co-occurrence with a pathogenic variant, CFTR 5T_TG11, has been reported (Narzi_2007). At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-30% of normal activity (Thelin_2007, Gene_2008, Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9439669, 19897426, 15758663, 18306312, 17594398, 20351098, 19724303, 17594397, 20351101, 17235394, 21983161, 19318035, 11938439, 25735457, 27264265, 25658530, 28736296, 29805046, 33374015). ClinVar contains an entry for this variant (Variation ID: 35824). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The CFTR c.14C>T variant is predicted to result in the amino acid substitution p.Pro5Leu. This variant has been reported in the compound heterozygous state in individuals with cystic fibrosis or chronic pancreatitis, typically with mild features and a second pathogenic variant that has been associated with severe forms of cystic fibrosis such as p.Phe508del (Gené et al. 2008. PubMed ID: 18306312; Thelin et al. 2007. PubMed ID: 17235394; Spicuzza et al. 2012. PubMed ID: 21983161; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies indicate this variant results in impaired CFTR function, presumably through a loss of glycosylation leading to intracellular retention of the receptor (Gené et al. 2008. PubMed ID: 18306312). However, to our knowledge there are no reports of individuals with classic cystic fibrosis who are homozygous for this variant. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161)
Comment:
The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 25658530 (2015), 25754095 (2015), 21983161 (2012), 19724303 (2010), 17331079 (2007), 17137500 (2006), 9439669 (1997)), atypical/mild CF symptoms (PMIDs: 31328366 (2019), 21983161 (2012), 19318035 (2009), 17594397 (2007)), and CFTR-related disorders (PMIDs: 34996830 (2022), 33374015 (2020), 27264265 (2016), 21520337 (2011), 15758663 (2005), 11938439 (2002)). Functional studies indicate this variant has deleterious effects on CFTR protein expression and ion channel activity (PMIDs: 29805046 (2018), 18306312 (2008), 17235394 (2007)). The frequency of this variant in the general population, 0.000054 (7/128930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Comment:
CFTR: PM3:Very Strong, PM2, PS3:Supporting
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). This variant is present in population databases (rs193922501, gnomAD 0.006%). This missense change has been observed in individuals with bronchiectasis, chronic pancreatitis, cystic fibrosis, and/or other CFTR-related disorders (PMID: 18306312, 19724303, 21520337, 21983161, 25910067). ClinVar contains an entry for this variant (Variation ID: 35824). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CFTR function (PMID: 17235394, 18306312, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.
Comment:
The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74.
Comment:
The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple individuals carrying a second CFTR alteration (six with p.F508del, two with p.W1282*, and one with p.R347P) with varying disease severity. The majority of individuals had pancreatic sufficiency, mild or no respiratory symptoms, normal lung function, and elevated sweat chloride levels (Spicuzza L et al. J. Cyst. Fibros., 2012 Jan;11:30-3; Sofia VM et al. Mol. Med., 2018 07;24:38). This variant has also been identified in multiple newborns with abnormal newborn screening results (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46; Paracchini V et al. JIMD Rep, 2012 Nov;4:17-23), as well as in an individual with idiopathic chronic pancreatitis (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In two functional studies, this variant demonstrated a reduced level of WT-CFTR protein function; in addition, the protein was predominantly localized intracellularly and demonstrated abnormal channel gating activity (Gené GG et al. Hum. Mutat., 2008 May;29:738-49; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). The p.P5L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 22, 2018). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Variant summary: CFTR c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes. c.14C>T has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, ICP, and CF (e.g. Chirico_2014, Narzi_2007, Sanz_2010, Schneider_2007, Spicuzza_2011). Multiple authors have indicated that the variant could cause a mild form of CF. These data indicate that the variant is very likely to be associated with disease. Co-occurrence with a pathogenic variant, CFTR 5T_TG11, has been reported (Narzi_2007). At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-30% of normal activity (Thelin_2007, Gene_2008, Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9439669, 19897426, 15758663, 18306312, 17594398, 20351098, 19724303, 17594397, 20351101, 17235394, 21983161, 19318035, 11938439, 25735457, 27264265, 25658530, 28736296, 29805046, 33374015). ClinVar contains an entry for this variant (Variation ID: 35824). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The CFTR c.14C>T variant is predicted to result in the amino acid substitution p.Pro5Leu. This variant has been reported in the compound heterozygous state in individuals with cystic fibrosis or chronic pancreatitis, typically with mild features and a second pathogenic variant that has been associated with severe forms of cystic fibrosis such as p.Phe508del (Gené et al. 2008. PubMed ID: 18306312; Thelin et al. 2007. PubMed ID: 17235394; Spicuzza et al. 2012. PubMed ID: 21983161; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies indicate this variant results in impaired CFTR function, presumably through a loss of glycosylation leading to intracellular retention of the receptor (Gené et al. 2008. PubMed ID: 18306312). However, to our knowledge there are no reports of individuals with classic cystic fibrosis who are homozygous for this variant. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| C FTR variants are associated with chronic bronchitis in smokers. | Saferali A | The European respiratory journal | 2022 | PMID: 34996830 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Andrological findings in infertile men with two (biallelic) CFTR mutations: results of a multicentre study in Germany and Austria comprising 71 patients. | Rudnik-Schöneborn S | Human reproduction (Oxford, England) | 2021 | PMID: 33374015 |
| Should isolated Pseudo-Bartter syndrome be considered a CFTR-related disorder of infancy? | Poli P | Pediatric pulmonology | 2019 | PMID: 31328366 |
| Trans-heterozygosity for mutations enhances the risk of recurrent/chronic pancreatitis in patients with Cystic Fibrosis. | Sofia VM | Molecular medicine (Cambridge, Mass.) | 2018 | PMID: 30134826 |
| Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators. | Han ST | JCI insight | 2018 | PMID: 30046002 |
| Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. | Raraigh KS | American journal of human genetics | 2018 | PMID: 29805046 |
| A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology. | Lucarelli M | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28736296 |
| CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. | Claustres M | Human mutation | 2017 | PMID: 28603918 |
| Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis. | Sofia VM | Molecular medicine (Cambridge, Mass.) | 2016 | PMID: 27264265 |
| Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
| A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. | Lucarelli M | Molecular medicine (Cambridge, Mass.) | 2015 | PMID: 25910067 |
| Insulin secretion abnormalities in exocrine pancreatic sufficient cystic fibrosis patients. | Wooldridge JL | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25754095 |
| Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection. | Chirico V | Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | 2015 | PMID: 25658530 |
| Cystic fibrosis newborn screening: distribution of blood immunoreactive trypsinogen concentrations in hypertrypsinemic neonates. | Paracchini V | JIMD reports | 2012 | PMID: 23430892 |
| Mild cystic fibrosis in patients with the rare P5L CFTR mutation. | Spicuzza L | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 21983161 |
| Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
| Biochemical basis of the interaction between cystic fibrosis transmembrane conductance regulator and immunoglobulin-like repeats of filamin. | Smith L | The Journal of biological chemistry | 2010 | PMID: 20351101 |
| Cystic fibrosis transmembrane conductance regulator interacts with multiple immunoglobulin domains of filamin A. | Playford MP | The Journal of biological chemistry | 2010 | PMID: 20351098 |
| A 10-year large-scale cystic fibrosis carrier screening in the Italian population. | Picci L | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2010 | PMID: 19897426 |
| The CFTR frameshift mutation 3905insT and its effect at transcript and protein level. | Sanz J | European journal of human genetics : EJHG | 2010 | PMID: 19724303 |
| Borderline sweat test: Utility and limits of genetic analysis for the diagnosis of cystic fibrosis. | Seia M | Clinical biochemistry | 2009 | PMID: 19318035 |
| N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. | Gené GG | Human mutation | 2008 | PMID: 18306312 |
| Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. | Narzi L | Clinical genetics | 2007 | PMID: 17594398 |
| Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. | Schneider M | Clinical genetics | 2007 | PMID: 17594397 |
| Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. | Alonso MJ | Annals of human genetics | 2007 | PMID: 17331079 |
| Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. | Thelin WR | The Journal of clinical investigation | 2007 | PMID: 17235394 |
| Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis. | Kraemer R | Respiratory research | 2006 | PMID: 17137500 |
| Reduced CFTR function and the pathobiology of idiopathic pancreatitis. | Cohn JA | Journal of clinical gastroenterology | 2005 | PMID: 15758663 |
| Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. | Audrézet MP | European journal of human genetics : EJHG | 2002 | PMID: 11938439 |
| High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. | Casals T | Human genetics | 1997 | PMID: 9439669 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs193922501 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.